Changes in PD-L1 and tumor mutational burden between paired samples and relationship to immune checkpoint inhibitor outcomes in non-small cell lung cancer.
Authors: Alessandro Di Federico, Stephanie Leigh Alden, James William Smithy, Biagio Ricciuti, Joao Victor Machado Alessi, Xinan Wang, Giuseppe Lamberti, Federica Pecci, Malini Marion Gandhi, Liam Flinn Spurr, Mark M. Awad
Journal: Journal of Clinical Oncology (2023)

9127 Background: Programmed cell death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key biomarkers of response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). How often PD-L1 and TMB values change across samples within individual patients (pts) and the impact of this variation on ICI outcomes are limited. Methods: Pts with NSCLC and multiple PD-L1 or TMB assessments at the Dana-Farber Cancer Institute were included. Clinicopathologic and genomic data were analyzed in association with PD-L1 and TMB changes. In patients with &gt; 2 samples, each sample was paired with the subsequent and each pair was analyzed independently. Minor and major changes in PD-L1 were defined as absolute changes of 10-49% and 50-100%, respectively. Results: The PD-L1 cohort included 402 sample pairs (median ΔPD-L1: 0; range: -90,+95%) and the TMB cohort included 413 sample pairs (median ΔTMB: 0 mut/Mb; range: -20.6,+24.5). Concordance between pairs was high for both PD-L1 ( R= 0.53, P &lt; 0.01) and TMB ( R= 0.80, P &lt; 0.01). Samples taken within &lt; 1 year had higher concordance for PD-L1 than samples taken ≥1 year apart (P &lt; 0.01), but length of time between biopsies did not impact TMB concordance. Minor or no changes in PD-L1 were observed in 82.3% of pairs; the frequency of major increases was 9.7% and major decreases was 8%. After dividing TMB into tertiles, 72.6% sample pairs showed no tertile change, 16% increased to a higher tertile, and 11.4% decreased to a lower tertile. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02), but PD-L1 and TMB did not change significantly with other intervening systemic therapies. Acquired copy number losses of the CD274 gene (encoding for PD-L1) were enriched in pairs with a major PD-L1 decrease (Q &lt; 0.05). Similarly, acquired loss of chromosome 9p (which contains the CD274 locus) correlated with a reduction in PD-L1, while 9p gains correlated with an increase in PD-L1 (P = 0.02). A total of 142 pts had multiple PD-L1 scores assessed before ICI initiation. Among pts with at least one PD-L1-positive sample (TPS ≥1%), the presence of another sample that was PD-L1 negative ( &lt; 1%) correlated with worse outcomes to ICI compared to pts with no PD-L1-negative samples: response rate was 11% vs 39% (P &lt; 0.01), median progression-free survival (mPFS) 2.7 vs 8.0 months (P &lt; 0.01), and median overall survival 13.6 vs 21.2 months (P = 0.05), respectively. Among pts with at least one PD-L1 TPS ≥1% and one &lt; 1%, cases where the last PD-L1 TPS before ICI was ≥1% achieved longer mPFS than if the pre-ICI sample was PD-L1 negative (3.6 vs 1.8 months, P = 0.03). Conclusions: Although PD-L1 and TMB generally had high intrapatient concordance across samples, significant changes in values occurred in some patients. Variations in PD-L1 influenced ICI outcomes, warranting an assessment proximal to ICI initiation whenever feasible.